Based on progress on progress made in the past funding period, development of new Tc-99m brain imaging agents specifically for in vivo imaging of CNS (central nervous system) receptors with SPECT (single photon emission computed tomography) is proposed. These new imaging agents will be useful tools for the pharmacological evaluation of CNS receptor functions in normal and disease states. This project combines the expertise of this laboratory in technetium chemistry, CNS receptor pharmacology and new radiopharmaceutical development. In this project, we have chosen to develop new Tc-99m labeled agents for dopamine reuptake sites and the 5-HT1A receptor, because they have clear clinical potential for the application of Tc-99m agents to the diagnosis of CNS abnormalities, and they serve as a suitable model system for testing the hypothesis that a Tc-99m based CNS receptor imaging agent can be developed. The specific aims for the next four years will be to design, synthesize and characterize Tc-99m labeled receptor specific agents for SPECT imaging of CNS 5-HT1A receptors and dopamine reuptake sites. Technetium-99m (T 1\2 = 6 hr, 140 Ke V) is the most commonly used radionuclide in diagnostic nuclear medicine. Its popularity is mainly due to the fact that the radionuclide is inexpensive, suitable for gamma camera detection an the physical half-life is compatible with the biological localization and residence time required for imaging. Currently, about 85% of routine nuclear medicine procedures are performed with radiopharmaceuticals based on Tc-99m. Improvements in the understanding of technetium chemistry have significantly enhanced the development of a new generation of technetium radiopharmaceuticals for clinical use and potentially will benefit millions of patients who receive Tc-99m agents for routine nuclear medicine diagnosis. Recently, evaluation of changes in CNS receptors using I-123 tracers in conjunction with in vivo SPECT imaging has demonstrated to be a useful diagnostic procedure. It provides unique information which is not easily available using other imaging modalities. This procedure extends beyond what is currently available in perfusion studies using Tc-99m HMPAO and ECD. Tc-99m labeled agents broaden the prospect of receptor imaging, because they are less expensive and more suitable for routine clinical use. Although it is a formidable challenge to incorporate a Tc complex moiety into a small receptor ligand and maintain the binding affinity of the original ligand, the overall objective is justified because the potential benefits for a large number of patients using nuclear medicine diagnostic procedures are enormous.